-%  ^ 


COLUMBIA  LIBRARIES  OFFSITE 

HEALTH  SCIENCES  STANDARD 


llliilillllll 


RC840.iv9^^^^^^^?olbutionstothe  ibc 'dntvetsiti?  ot  CbtcaQO 


RECAP 


CONTRIBUTIONS  TO  THE  PHYSL 
OLOGY  OF  THE  STOMACH 


A  DISSERTATION 

SUBMITTED  TO  THE  FACULTY 

OF  THE  OGDEN  GRADUATE  SCHOOL  OF  SCIENCE 

IN  CANDIDACY  FOR  THE  DEGREE   OF 

DOCTOR  OF   PHILOSOPHY 

DEPARTMENT  OF  PHYSIOLOGY 


BY 


ANDREW  CONWAY  IVY 


o 

b 


Private  Edition,  Distributed  By 

THE  UNIVERSITY  OF  CHICAGO  LIBRARIES 

CHICAGO,  ILLINOIS 

Reprinted  from 

The  Akchives  of  Internal  Medicine 

Vol.  XXV,  January  1920 


T«iT:fei»  University 


Columliia  ^nibersiitp 
in  ttie  Citp  of  i^eto  l^orfe 

CoUese  of  S^t^sitismsi  anb  burgeons: 


3^ef  erence  l^ibrarp 


Ube  laniversitp  of  CbicaQO 


CONTRIBUTIONS  TO  THE  PHYSl 
OLOGY  OF  THE  STOMACH 


A  DISSERTATION 

SUBMITTED   TO   THE   FACULTY 

OF   THE   OGDEN   GRADUATE   SCHOOL  OF   SCIENCE 

IN   CANDIDACY   FOR   THE   DEGREE    OF 

DOCTOR   OF    PHILOSOPHY 

DEPARTMENT  OF  PHYSIOLOGY 


BY 

ANDREW  CONWAY  IVY 


Private  Edition,  Distributed  By 

THE  UNIVERSITY  OF  CHICAGO  LIBRARIES 

CHICAGO,  ILLINOIS 


Reprinted  from 

The  Archives  of  Internal  Medicine 

Vol.  XXV,  January  1920 


THE  UNIVERSITY  OP  CHICAGO  PRESS 
CHICAGO.  ILLINOIS 


TEE  BAKER  &  TAYLOR  COMPANY 

NEW  TORE 

THE  CAMBRIDGE  UNIVERSITY  PRESS 

LONDON 

THE  MARUZEN-KABTJSHIKT-KAISHA 

TOKYO,  OSAKA,  KYOTO,  KUKUOKA,  BENDAJ 

THE  MISSION  BOOK  COMPANY 

SHANGHAI 


CONTRIBUTIONS    TO    THE     PHYSIOLOGY     OF    THE 

STOMACH 

LII.     STUDIES     ON     GASTRIC     ULCER  * 
A.     C     IVY,     Ph.D. 

CHICAGO 

The  studies  on  gastric  ulcer  as  presented  here  are  the  first  of  a 
series  of  studies  on  the  pathologic  physiology  of  the  stomach  and 
duodenum  in  the  condition  of  ulcer  of  these  parts  of  the  gastro- 
intestinal tract. 

I.     THE    OCCURENCE    OF    ULCER    AND    OTHER    PATHOLOGIC    LESIONS 

IN     THE     STOMACH     AND     THE     DUODENUM     OF     THE     DOG 

AS     JUDGED     FROM     ONE     THOUSAND     NECROPSIES 

In  a  series  of  studies  to  be  made  on  a  pathologic  physiologic  con- 
dition it  is  obviously  essential  to  make  a  study  of  the  frequency  of 
the  occurrence  of  that  condition  in  the  animal  used.  A  large  amount 
of  work  has  been  done  on  gastric  ulcer  in  which  the  dog  has  been 
the  chief  experimental  animal.  There  are  only  two  reports  in  the 
literature  concerning  the  frequency  of  the  occurrence  of  ulcer  in 
the  dog.  Turck^  reports  a  series  of  necropsies  on  189  healthy  and 
82  diseased  dogs  in  which  the  findings  of  "peptic  ulcer"  were  abso- 
lutely negative.  Other  pathologic  lesions,  if  they  occurred,  are  not 
reported.  Mann^  reports  a  series  of  more  than  two  hundred  normal 
dogs  and  cats  in  which  no  "lesion  of  the  gastric  mucosa  was  found 
at  necropsy."  From  the  findings  of  these  two  observers  one  might 
conclude  that  the  occurrence  of  lesions  of  the  gastric  mucous  mem- 
brane of  the  dog  are  very  rare.  Since  the  data  ofifered  in  the  literature 
is  meager,  it  was  considered  important  to  ascertain  more  completely 
the  occurrence  of  lesions  of  the  gastric  mucous  membrane  in  the  dog. 

METHODS 

The  stomach  and  duodenum  of  healthy,  diseased  and  experimental 
dogs  was  removed  immediately  after  death  and  placed  in  cold  running 
water  where  they  were  examined  immediately,  or  always  within  one 
hour  after  removal.     Ouite  a  number  of  stomachs  were  examined  a 


*From  the  Hull  Physiological  Laboratory  of  the  University  of  Chicago. 

1.  Turck,  F.  B.:    J.  A.  M.  A.  67:1784   (Dec.  9)   1916. 

2.  Mann,  F.  C. :    J.  Exper.  M.  23:203  (Feb.)  1916. 


longer  period  after  death  than  one  hour,  but  observations  on  these 
were  not  recorded  because  of  the  possibiHty  that  any  lesion  present 
might  be  the  effect  of  autodigestion. 

The  lesions  observed  were  classified  as  follows:  (1)  Petechial 
hemorrhage,  applied  to  the  condition  in  which  the  red  blood  corpuscles 
are  abundantly  packed  in  the  tissues  of  the  mucosa  and  lie  in  the 
mucosa  adjacent  to  the  lumen;  (2)  superficial  hemorrhagic  erosion, 
applied  to  the  condition  in  which  there  is  an  evident  petechial  hemor- 
rhage accompanied  by  a  superficial  erosion  of  the  cells  of  the  mucous 
membrane;  (3)  acute  ulcer,  applied  to  the  condition  in  which  there 
is  a  well  defined  break  in  the  continuity  of  the  mucous  membrane; 
(4)  chronic  ulcer,  applied  to  the  condition  in  which  the  edges  of 
the  ulcer  are  raised,  undermined  and  thickened,  and  the  base  of  the 
ulcer  indurated;  (5)  diffuse  inflammation,  applied  to  the  condition 
generally  referred  to  as  gastritis  in  which  there  occurs  a  swelling 
and  hyperemia  of  the  mucous  membrane  together  with  the  production 
of  a  viscid  adhesive  mucus  exudate  and  in  acute  cases  with  the 
occurrence  of  petechial  hemorrhages  and  superficial  erosions;  (6)  and 
tumors  involving  the  mucosa.  I  agree  with  Bolton^  that  it  is  neither 
useful  nor  correct  to  call  a  superficial  hemorrhagic  erosion  an  ulcer. 

RESULTS 

Table  1  shows  the  occurrence  of  pathologic  lesions  in  the  stomach 
and  duodenum  of  healthy  dogs  that  had  been  subjected  to  ether  anes- 
thesia for  a  period  of  two  or  three  hours,  while  students  used  them 
for  acute  laboratory  experimentation. 

TABLE  1. — Showing  Lesions  of  the  Stomach  and  Duodenum    (900  Dogs) 


Lesions 

Cardia 

Fundus 

Pylorus 

Duodenum 

Remarks 

No. 

% 

No. 

% 

No. 

% 

No. 

% 

Petechial  hemorrhages — 
Superficial     hemorrhagic 

11 
1 

1.2 
0.09 

1 
4 

0.09 
0.44 

2.6 

23 
1 

.     4 
3 

2.9 

2.5 
0.09 

0.44 
0.33 

13 
6 

23 

1.4 
0.6 

2.5 

Old  emaciated 

Diffuse  inflammation 

dog 
Adenomatous 

polyps 

The  petechial  hemorrhages  and  hemorrhagic  erosions  occurred 
chiefly  in  the  last  2  inches  of  the  pyloric  portion  of  the  stomach  and 
in  the  first  inch  of  the  duodenum.  In  the  case  of  the  acute  ulcer 
of  the  pyloric  portion  of  the  stomach  there  were  two  ulcers  (2  by 
1  mm.),  involving  the  entire  thickness  of  the  mucosa  within  one-half 
inch  of  the  sphincter.     The  stomach  was  taken  from  on  old  emaciated 


3.  Bolton:    Quart.  J.  Med.  5:434,  IQIL 


animal.  No  apparent  cause  for  the  gastritis  could  be  found.  Worms 
accompanied  the  enteritis  in  all  except  five  animals,  and  may  have 
been  the  cause  in  most  cases.* 


TABLE  2. — Lesions   Occurring  in  Thyroid   Parathyroidectomized   Dogs 
(Twenty-Four  Dogs)* 


Stomach 


Stomach, 
No. 


Duodenum, 

No. 


Petechial  hemorrhages 16 

Superficial  hemorrhagic  erosions |  13 

Acute  ulcer i  1 

Diffuse  inflammation 9 


*  One  acute  ulcer,  15   x   3  mm.,  almost  perforated  was  found  in  the  fundus.      Otherwise 
aU  the  lesions  in  the  stomach  were  confined  to  the  pyloric  portion. 

Table  2  shows  the  occurence  of  ulcer  and  of  lesions  of  the  mucous 
membrane  of  the  stomach  and  duodenum  in  animals  dying  of  thyroid 
parathyroidectomy.  The  paramount  symptom  that  was  manifested  in 
the  animals  was  depression,  as  reported  by  Carlson,^  only  60  per  cent, 
of  them  showing  tetany.  These  animals  lived  from  three  to  twenty 
days.  The  severity  of  the  intestinal  findings  was  directly  portional 
in  most  cases  to  the  longevity  of  life  following  the  operation. 

Eight  out  of  forty  dogs  dying  of  distemper  (snuffles)  showed 
petechial  hemorrhages  and  superficial  hemorrhagic  erosions  of  the 
pyloric  and  duodenal  mucous  membrane.  Acute  gastritis  and  enteritis 
was  present  in  every  dog  in  this  series.  Hypoacidity  is  a  constant 
occurrence  in  these  animals.  I  have  seen  several  cases  in  which  raw 
meat  would  pass  through  the  gastro-intestinal  tract  of  a  dog  sick 
with  distemper  without  being  changed  in  color.  Diarrhea  is  also 
present  in  practically  every  case,  as  is  anorexia  and  emaciation. 

In  ten  dogs  dying  of  shock  and  symptoms  of  raised  intracranial 
pressure  following  cerebral  ablations,  every  one  showed  petechial 
hemorrhages  and  superficial  erosions  of  the  fundic  and  pyloric  mucous 
membrane.  In  four  of  these  dogs  the  stomach  was  acutely  dilated. 
No  free  acid  was  present  in  the  stomach  of  these  animals. 

Out  of  twenty  dogs  that  had  been  injected  intravenously  with 
ether  twenty-four  hours  previous  to  death,  five  showed  petechial  hem- 
orrhages and  superficial  erosions  of  the  fundic  and  pyloric  mucous 
membrane. 

Superficial  hemorrhagic  erosions  occur  frequently  in  dogs  dying 
of  experimental  diabetes. 

A  deeply  eroded  and  indurated  ulcer  (4  by  6  mm.),  typically 
chronic,  was  found  in  the  first  quarter  of  an  inch  of  the  duodenum 


4.  Food  was  present  in  the  stomachs  of  about  one  half  of  the  animals.    The 
lesions  had  no  relation  to  the  presence  of  food,  however. 

5.  Carlson.  A.  J.:    Am.  J.  Physiol.  30:   1912. 


in  a  cachectic  dog  whose  pancreatic  ducts  had  been  ligated  five  months 
previously  and  who  had  been  kept  on  a  diet  of  bread  and  milk. 
Hypoacidity  was  present  in  this  dog.  The  dog  died  of  acute  stomatitis 
accompanied  by  rapid  emaciation.  The  stomach  and  duodenum  of 
twenty-four  dogs,  in  which  the  pancreatic  ducts  had  been  ligated,  were 
examined  without  finding  ulcer.  Four  of  these  animals  showed  super- 
ficial erosions.  In  these  dogs  emaciation  was  marked  and  they  died  of 
distemper.  The  other  animals  were  killed  in  other  experiments,  no 
lesions  being  present.  With  the  exception  of  six  of  these  animals,  the 
pancreas  was  from  macroscopic  appearance  atrophic  and  fibrotic. 
Jona®  reports  the  presence  of  ulcers  in  the  duodenum  and  small  intes- 
tine following  ligation  of  one  pancreatic  duct.  From  his  picture  and 
his  description,  I  am  led  to  believe  that  what  he  called  ulcers  were 
nothing  more  than  Peyer's  patches,  which  occur  in  the  duodeum  of  the 
dog,  made  more  conspicuous  by  emaciation  and  postmortem  digestion. 
These  patches  are  easily  mistaken  for  ulcers,  if  a  microscopic  study 
is  not  made. 

My  observations  on  suprarenalectomized  animals  partly  confirm 
those  of  Mann.-  In  forty  suprarenalectomized  dogs  I  have  only  seen 
one  acute  ulcer  and  twenty  instances  of  petechial  hemorrhage  and 
hemorrhagic  erosion  of  the  gastric  and  duodenal  mucous  membrane, 
which  is  less  frequent  than  reported  by  Mann. 

Dogs  dying  immediately  after  section  of  the  vagi  and  splanchnics 
not  infrequently  show  petechial  hemorrhages  of  the  pyloric  and  duo- 
denal mucous  membrane.  But  in  ten  dogs  that  died  or  were  killed 
from  one  week  to  four  months  following  double  vagotomy  and  splanch- 
notomy  with  extirpation  of  the  celiac  plexus,  no  gastric  or  duodenal 
lesions  were  found.  Durante'  reports  that  he  observed  lesions  that 
were  similiar  to  acute  and  chronic  ulcers  in  man.  He  does  not  state 
how  long  the  ulcers  were  present  and  only  states  that  such  animals 
survive  a  short  time.  Most  of  my  animals  lived  indefinitely  and  the 
nerve  sections  were  verified  at  necropsy.  Such  animals  become  cachec- 
tic, however,  and  have  to  be  cared  for  rather  carefully  for  some  time 
in  order  to  keep  them  in  a  normal  state  of  health.* 

In  a  personal  communication  from  Dr.  S.  A.  Mathews,  I  was  told  that  in 
Eck  fistula  dogs,  which  are  kept  alive  for  a  long  period  on  a  diet  of  bread  and 
milk  and  which  are  emaciated  and  cachectic,  chronic  ulcers  of  the  stomach  are 
frequently  found. 


6.  Jona,  J.  L.:    AI.  J.  Austraha  1:316  (April  19)  1919. 

7.  Durante,  L. :    Surg.,  Gyn,  Obst.  22:399  (April)   1916. 

8.  In  an  emaciated  dog  with  gastrostomy  and  both  splanchnics  cut,  Dr.  A.  B. 
Luckhardt  found  a  chronic  ulcer  about  one  inch  from  the  gastrostomy.  The 
ulcer  was  about  to  perforate. 


The  three  tumor  formations  found  were  adenomatous  polyps  which 
were  confined  in  each  case  to  the  mucosa  of  the  pyloric  portion  of 
the  stomach. 

No  scars  were  found  in  the  stomach  or  duodenal  mucous  mem- 
brane. These  were  looked  for  as  probable  evidence  of  healed  acute 
ulcers.     Such  scars  are  reported  to  occur  frequently  in  man. 

SUMMARY     AND     DISCUSSION 

It  is  apparent  from  the  results  of  this  study  that  chronic  ulcer 
of  the  stomach  and  duodenum  in  healthy  dogs  and  even  diseased 
dogs,  if  it  occurs  at  all,  is  very  rare.  In  diseased  and  cachectic  experi- 
mental animals  only  two  marked  ulcerations  were  found :  one,  very 
acute  and  almost  perforating,  the  second,  typically  chronic.  On  the 
other  hand,  petechial  hemorrhages  and  superficial  hemorrhagic  ero- 
sions do  occur  in  the  gastric  and  duodenal  mucosa  of  the  healthy 
dog.  (I  have  seen  them  in  the  mucosa  of  the  stomach  even  though  the 
animal  had  not  been  subjected  to  ether  anesthesia  previously.)  These 
lesions,  however,  occur  more  frequently  in  experimental,  diseased  and 
cachetic  animals. 

Comparing  these  observations  with  those  reported  to  occur  in 
man,  it  is  seen  that  the  dog  is  much  less  subject  to  gastric  lesions  than 
man.  According  to  Adami^  "hemorrhages  into  the  stomach  wall  are 
quite  common"  in  man,  and  Birch-Hirschfield^°  reports  that  they  are 
found  -in  50  per  cent,  of  cadavers.  Osler^^  states  that  hemorrhagic 
erosions  are  common.  Chronic  ulcer  occurs  in  man  as  often  as  from 
2  to  4  per  cent.  Why  there  is  such  a  difference  between  man  and 
dog  is  a  matter  open  for  speculation.  If  gastric  juice  digestion  was 
a  basic  factor,  we  would  expect  more  ulcers  in  the  dog  than  in 
man  as  the  dog's  acidity  is  on  the  average  greater  than  man's.  The 
dog  being  an  animal  generally  of  higher  resistance  and  less  subject  to 
dietary,  toxic  and  nervous  factors,  which  cause  gastric  disturbance  of 
motor,  secretory  and  circulatory  activity,  than  man,  we  would  expect 
to  find  fewer  ulcers.  The  dog  not  being  so  subject  to  focal  infections 
and  hemorrhagic  erosions  as  man,  the  dog  would  be  less  likely  to  have 
an  ulcer  hematogenous  in  origin.  Also,  the  dog  being  less  subject  to 
nervous  influences,  which  cause  hypomotility  and  hyposecretion,  there 
would  be  less  chance  to  infect  a  point  of  lowered  resistance,  a  petechial 
hemorrhage  or  erosion,  by  bacteria   swallowed.     These  observations 


9.  Adami,  J.:    Principles  of  Pathology,  Philadelphia,  Lea  &  Febiger,  1911,  2: 
414. 

10.  Birch-Hirschfeld :    loc.  cit.,  Adami. 

11.  Osier,   W. :    The   Principles   and    Practice   of   Medicine,    New   York,    D. 
Appleton  &  Co.,  1916,  pp.  490,  447,  480. 


suggest  at  least  that  there  is  some  factor  present  in  man  causing  the 
chronicity  of  the  ulcer  which  is  absent  in  the  dog ;  also,  that  if  chronic 
ulcer  can  be  produced  in  the  dog's  stomach  or  duodenum,  it  can  be 
produced  in  man  by  the  same  method. 

The  fact  that  chronic  gastric  ulcer  does  not  occur  and  that  gastric 
carcinoma  is  not  found  in  the  dog  is  comparative  evidence,  I  take  it, 
in  favor  of  Mayo  Robson's^^  theory  of  the  etiology  of  carcinoma  of 
the  stomach  in  man.  Mayo  Robson  suggested  that  gastric  ulcer  was 
the  source  of  gastric  carcinoma.  Wilson  and  McCarthy^^  have  pre- 
sented evidence  in  support  of  this  theory. 

2.     THE   EXPERIMENTAL   PRODUCTION   OF  CHRONIC  GASTRIC  ULCER 

IN    THE   DOG 

Petechial  hemorrhages,  superficial  hemorrhagic  erosions  and  acute 
ulcers  have  been  produced  experimentally'  in  many  ways :  mechanically, 
chemically,  by  heat,  drugs,  toxins,  peptones,  serums,  by  section  of  the 
vagi  and  the  splanchnics,  by  embolism  and  thrombosis,  anemia,  by 
feeding  bacteria,  by  the  intravenous  injection  of  specific  and  -^non- 
specific bacteria,  by  abrasions,  by  lesions  to  the  central  nervous  system, 
by  removal  of  the  suprarenals  and  parathyroids,  and  by-  many  other 
methods.  In  other  words,  they  are  produced  by  anything  that  causes 
a  local  necrosis  of  the  membrane  by  direct  toxic  or  chemical  action  on 
the  mucosal  cells  or  by  interfering  or  disturbing  the  normal  condition 
of  the  capillaries  of  the  mucosa.  All  biologic  methods  of  producing 
the  hemorrhages  seem  to  point  toward  a  marked  susceptibility  of  the 
gastric  and  duodenal  mucosal  capillaries  to  injury  by  toxic  and  nervous 
influences. 

Although  acute  ulcers  have  been  produced  in  many  ways,  few 
investigators  have  claimed  to  have  produced  chronic  ulcers  of  the 
gastric  and  duodenal  mucosa.  Bolton^*  and  Friedman  and  Hamburger^^ 
were  able  to  delay  the  healing  of  experimental  acute  ulcers  by  pro- 
ducing partial  pyloric  stenosis.  Turk^  reported  that  he  was  able  to 
produce  perforating  ulcers  of  the  duodenum  and  stomach  by  feeding 
B.  coli.  Durante,^  by  ligating  and  cutting  the  splanchnic  nerves,  reports 
the  production  of  chronic  ulcers.  Rosenow^*'  has  reported  the  produc- 
tion of  gastric  and  duodenal  ulcers  that  "resemble  those  in  man  in 
location  and  tend  to  become  chronic,  to  perforate  and  to  cause  hemor- 
rhage" by  the  intravenous  injection  of  alleged  specific  streptococci. 


12.  Robson,  A.  W.  M. :    Lancet  2:1547,  1904. 

13.  Wilson,  L.,  and  McCarthy,  W.  C. :    Am.  J.  M.  Sc,  846  (Dec.)   1909. 

14.  Bolton:    Proc.  Roy.  Soc,  Lond.  82:236,  1909. 

15.  Friedman,  J.  C,  and  Hamburger,  W.  W. :    J.  A.  M.  A.  62:380  (Aug.  1) 
1914 

16.  Rosenow,  E.  C:   J.  Infect.  Dis.  19:333  (Sept.)  1916. 


The  chief  views  held  at  the  present  time  concerning  the  etiology  of 
chronic  gastric  ulcer  are  as  follows:  (1)  Infection  of  the  mucous 
membrane  through  the  blood  by  specific  or  nonspecific  bacteria  from 
a  focal  infection  is  the  primary  factor  and  the  source  of  reinfection; 
(2)  the  digestive  action  of  the  gastric  juice  on  mucosal  cells  that  have 
had  their  normal  resistance  to  acid  peptic  digestion  diminished  in  some 
way;  (3)  a  localized  trophic  disturbance  is  responsible  for  the  chron- 
icity  of  the  ulcer;  (4)  the  infection  of  the  mucous  membrane  by 
swallowed  bacteria. 

Most  investigators  in  this  field  agree  with  Bolton^"  that  chronic 
ulcer  originates  from  an  acute  lesion  and  that  most  of  the  acute  lesions 
heal  rapidly. 

This  study  was  undertaken  as  an  attempt  to  throw  more  light  on 
the  experimental  production  of  chronic  ulcer  in  the  dog. 

METHODS    AND    RESULTS 

Healing  of  Experimental  Acute  Ulcers. — The  time  required  for  the 
healing  of  acute  ulcer  produced  by  Roth's  method  (the  injection  sub- 
mucously  of  1.0  c.c.  of  a  5  per  cent,  silver  nitrate  solution)  in  the 
fundic  and  pyloric  portions  of  the  stomach  and  in  the  duodenum. 
Ulcers  made  in  the  mucous  membrane  of  the  fundic  portion  of  the 
stomach  healed  in  from  nine  to  thirteen  days ;  when  ulcers  were  made 
in  the  pyloric  portion  of  the  stomach,  healing  required  from  twelve  to 
eighteen  days ;  if  the  dogs  had  the  distemper,  healing  required  from 
eighteen  to  twenty-two  days.  In  the  duodenum  from  sixteen  to  twenty- 
four  days  were  required  for  the  healing  of  the  ulcer. 

This  difference  in  the  rate  of  healing  is  explained,  I  believe,  by 
the  anatomy  and  physiology  of  the  different  portions  and  the  way  in 
which  ulcers  of  the  mucosa  heal.  The  manner  of  healing  has  been 
described  in  detail  by  Bolton^'*  and  Griflfini  and  Vassale.^* 

Aseptic  Embolism. — Injections  of  finely  divided  animal  charcoal 
suspensions  were  made  into  the  branches  of  the  gastro-epiploic  arteries 
with  negative  results.  Suspensions  of  lead  chromate  and  pigments 
were  injected  into  branches  of  the  gastro-epiploic  arteries  with  result- 
ing petechial  hemorrhages  and  hemorrhagic  erosions.  Acute  ulcers 
resulted  in  three  of  the  animals  injected  with  lead  chromate.  The 
results  with  lead  chromate  and  pigments  confirm  the  observations  of 
Cohnheim^^  and  Klebs  and  Welti. 2°  Why  the  injection  of  animal 
charcoal  gave  negative  results  cannot  be  stated.     The  findings  suggest 


17.  Bolton :   Ulcer  of  the  Stomach,  London,  1913. 

18.  Griffini  and  Vassale:    Ziegler's  Beitr.  3:425. 

19.  Cohnheim:    Lect.  on  Gen.  Path.  (New  Sydenham  Soc.)  3:878,  1890. 

20.  Klebs  and  Welti:  Handb.  d.  path.  Anat.,  1869. 


8 

that  effects  produced  by  pigments  and  lead  may  be  toxic  and  that  an 
embolism  produced  by  an  inert,  nontoxic  substance,  charcoal,  will  not 
result  in  hemorrhage  or  acute  ulcer. 

Ligation  of  Blood  Supply. — Six  to  eight  of  the  branches  of  the 
gastro-epiploic  vessels  supplying  the  pyloric  portion  of  the  stomach 
were  ligated  with  negative  results.  This  confirms  the  results  of 
Littauer^^  who  found  that  the  blood  supply  to  one  third  of  the  stomach 
could  be  cut  off  without  producing  dileterious  effects  and  demonstrates 
a  marked  freedom  of  anastomosis. 

Silver  nitrate  ulcers  were  made  in  such  an  area  to  which  the  large 
blood  vessels  had  been  ligated  with  the  result  that  they  healed  in  normal 
time.  The  ulcers  were  made  at  the  same  time  that  the  vessels  were 
Hgated. 

Partial  Pyloric  Stenosis  and  Healing  of  the  Ulcer. — The  effect  of 
partial  pyloric  stenosis  on  the  rate  of  the  healing  of  the  ulcer  was 
studied  in  eight  dogs.  In  five  the  healing  time  of  the  ulcer  was  delayed 
from  two  to  four  weeks.  No  marked  induration  of  the  edges  occurred 
in  any  case.  The  ulcers  in  the  three  dogs  which  did  not  manifest  rapid 
loss  of  weight  healed  in  normal  time.  To  ascertain  the  condition  of 
the  ulcer,  the  dog  was  killed  in  some  cases,  in  other  cases  operated  on 
aseptically  and  the  ulcer  examined  by  direct  inspection  through  an 
incision  in  the  stomach  wall.  These  findings  confirm  the  observations 
of  Bolton^*  and  Friedman  and  Hamburger,^^  who  report  delayed  heal- 
ing in  acute  experimental  ulcers  accompanied  by  partial  pyloric  stenosis. 
Bolton  reports  delayed  healing  only,  while  Friedman  reports  a  chronic 
ulcer  at  eight  weeks  after  the  production  of  the  acute  ulcer.  Bolton 
accounts  for  the  delayed  healing  as  "due  to  necrosis  of  the  base  of 
the  ulcer  or  excessive  formation  of  sclerotic  tissue  therein,  such  con- 
ditions being  the  result  of  the  low  resistance  which  the  connective 
tissues  possess  to  digestion  by  gastric  juice,  or  possibly  in  some  cases 
to  a  secondary  bacterial  infection."  Friedman  and  Hamburger  account 
for  the  delayed  healing  by  the  prolonged  action  of  the  gastric  juice 
and  hyperperistalsis.  Loss  of  weight  and  disturbed  nutrition,  which 
I  observed  in  my  animals  and  which  is  reported  by  both  of  the  above 
investigators,  although  not  emphasized,  and  bacterial  infection  of  the 
acute  ulcer  must  also  be  considered  as  possible  factors  in  the  delayed 
healing  following  partial  pyloric  stenosis. 

Injections  of  Bacteria. — Injections  of  streptococci  (one  tube  of  a 
twenty-four-hours-old  culture  in  dextrose  ascites  broth)  were  made 
into  two  or  three  branches  of  the  gastro-epiploic  arteries  in  a  series  of 


21.  Littauer:    Virch.  Arch.  195:   No.  2,  328. 


dogs  with  negative  results.  The  dogs  were  killed  from  two  to  four 
weeks  after  the  injection,  so  if  any  acute  effects  were  produced,  they 
did  not  persist  nor  leave  scars.  In  two  dogs  killed  twenty-four  hours 
after  the  operation  petechial  hemorrhages  were  found.  Perigastritis 
resulted  in  every  case.  Two  strains  of  streptococci  were  used,  one  a 
Streptococcus  viridans  isolated  from  a  tonsil,  the  other  a  Streptococcus 
hemolyticus  from  a  case  of  septicemia.  Dr.  Clawson  of  the  department 
of  bacteriology,  from  whom  the  bacteria  were  obtained,  stated  that 
both  were  fatal  for  rabbits.  The  5.  viridans  when  injected  (three 
tubes  of  a  twenty-four-hours-old  culture  of  dextrose  ascites  broth) 
into  dogs  caused  no  symptoms;  the  6^.  hemolyticus  when  injected  into 
dogs  caused  a  rise  in  temperature,  inactivity  and  loss  of  appetite  of 
three  days'  duration.  Although  the  bacteria  were  virulent  enough  to 
produce  a  dense  fibrinous  and  fibrous  perigastritis  at  the  site  of  injec- 
tion, no  acute  ulcers  of  the  stomach  resulted.  These  results  suggest 
that  either  a  markedly  virulent  or  a  specific  bacterium  is  required  to 
produce  an  acute  ulcer  of  the  stomach.  I  have  injected  streptococci 
beneath  the  skin  and  the  mucosa  of  the  stomach  at  the  same  time  and 
in  the  same  dog;  in  the  former  instance  an  abscess  developed,  while 
nothing  resulted  from  the  submucosal  injection. 

Feeding  Bacteria. — The  effect  of  feeding  bacteria  to  dogs  in  which 
an  experimental  abrasion  of  the  pyloric  and  duodenal  mucous  mem- 
brane had  been  made  was  studied.  The  laceration  was  made  under 
aseptic  procedure  through  an  incision  in  the  anterior  wall  of  the  stom- 
ach by  pinching  and  tearing  the  mucosa  with  a  hemostat  or  extirpating 
it  with  the  knife.  Ten  tubes  of  a  twenty-four-hour-old  culture  of  strep- 
tococcus were  given  daily  by  the  stomach  tube  at  a  time  when  the 
stomach  was  empty.  This  was  done  in  five  healthy  dogs  with  negative 
results,  the  laceration  healing  in  from  six  to  ten  days  and  the  extirpa- 
tions in  from  twelve  to  fifteen  days.  In  other  words,  Wilkensky  and 
Geist's^^  observations  were  confirmed.  The  work  was  about  to  be 
given  up  when  a  sixth  dog  developed  distemper  after  the  operation 
and  had  recovered  three  weeks  later.  The  dog  was  killed  and  a 
necropsy  was  made  six  weeks  after  the  operation.  A  large  hyperemic, 
edematous,  inflamed  ulcer  (three-quarters  of  an  inch  in  diameter) 
was  found  at  the  point  of  laceration.  This  dog  had  been  fed 
Streptococcus  viridans,  which  Dr.  Clawston  isolated  from  the  deep 
tissues  adjacent  to  the  ulcer.  The  work  was  continued  on  two  other 
distemper  dogs  and  in  two  cachectic  dogs  with  ligated  pancreatic  ducts. 
Six  weeks  after  the  production  of  the  acute  ulcer  a  necropsy  was 
done  on  one  of  the  distemper  dogs.     It  revealed  an  ulcer  with  con- 


22.  Wilkensky,  A.  O.,  and  Geist,  S.  H. :  J.  A.  M.  A.  66:1382  (April  29),  1916. 


10 

gested  and  edematous  edges  with  a  thickened  base.  This  dog  had  been 
fed  Streptococcus  hemolyticus  which  was  isolated  from  the  deep  tissues 
about  the  edges  of  the  ulcer  by  Rosenow's  technic.^^  The  second  dis- 
temper dog  which  recovered  from  the  distemper  four  weeks  after  the 
operation  was  killed  four  weeks  later,  or  eight  weeks  after  the  pro- 
duction of  the  abrasion  of  the  mucosa,  and  a  healing  ulcer  (Fig.  1) 


■ 

j^^^^-mm-— 

■P 

V'     ^.         A 

%1 

^f'^ 

^" ""  j^i 

m 

y^ 

a,  ^'''''    ^^^^^^^1 

Fig.  1. — Chronic  ulcer   (eight  weeks)   of  the  pyloric  portion  of  the  stomach 
produced  experimentally. 


Fig.    2. — Chronic    ulcer    (ten    weeks)    of    the    duodenum    produced    experi- 
mentally. 

was  found  at  the  site  of  the  abrasion.  The  edges  were  congested, 
edematous  and  markedly  indurated.  The  cachectic  ligated  pancreatic 
duct  dog  showed  at  the  site  of  the  duodenal  abrasion,  which  was  made 
in  this  dog,  an  indurated  ulcer  with  edematous  edges  (Fig.  2)  ten 
weeks  after  the  production  of  the  lesion.  This  dog  continued  to  get 
more  emaciated  and  weaker  until  it  was  killed. 


23.  Rosenow.    Jour.  Infect.  Dis.  17:219,  1915. 


11 

The  gastric  juice  and  stomach  contents  of  these  dogs  were  exam- 
ined at  intervals  for  free  acid.  Free  acid  was  not  found  at  any  time 
during  the  attack  of  distemper  or  during  marked  cachexia.  This  fact 
IS  well  known  to  anyone  who  has  worked  with  Pavlov  pouch  dogs  sick 
with  distemper  or  showing  a  disturbance  of  nutrition. 

This  study  is  being  continued  by  a  new  method  that  will  be  more 
subject  to  experimental  control. 

DISCUSSION 

The  chronic  ulcers  produced  in  this  study  suggest  that  two  other 
factors  are  necessary  other  than  an  abrasion  with  a  trophic  disturbance, 
infection  via  mouth  or  blood  stream  and  acidity,  namely,  (1)  a  general 
lowered  resistance,  and  (2)  a  temporary  hypoacidity  or  achylia.  The 
animals  in  which  it  was  possible  to  delay  healing  of  the  acute  lesion 
and  to  cause  it  to  assume  signs  of  chronicity  by  feeding  streptococci 
were  diseased  and  cachectic,  and  showed  no  free  acid  in  their  gastric 


Fig.  3. — Ulcer  found  by  Dr.  A.  B.  Luckhardt  one  inch  from  a  gastrostomy 
opening  in  an  emaciated  dog  witli  both  splanchnics  sectioned. 

juice  or  contents.  It  is  to  be  recalled  that  it  was  observed  in  the  first 
study  on  the  occurrence  of  gastric  and  duodenal  lesions  that  erosions 
are  much  more  frequent  in  the  experimental,  diseased  and  cachectic 
animals.  It  is  well  known  that  diseased  and  cachectic  animals  show 
gastric  juice  that  is  deficient  in  free  acidity  and  often  entirely  absent. 
This,  of  course,  makes  it  possible  for  any  bacteria  swallowed  or  admin- 
istered to  become  implanted  in  the  abrasion  or  local  area  of  hemorrhage 
or  erosion,  if  present — free  acid  to  the  extent  that  occurs  normally 
in  the  stomach  being  incompatible  with  life  for  most  bacteria.  Further, 
it  should  be  pointed  out  that  an  infected  lesion  in  a  pathologic  mucous 
membrane — for  the  mucosa  of  the  stomach  is  pathologic  when  it  is  not 
secreting  its  normal  gastric  juice — is  more  likely  to  assume  signs  of 
chronicity  and  to  become  chronic  than  a  lesion  in  a  normal  mucous 
membrane  functioning  normally.  Therefore,  given  an  abrasion  of  a 
pathologic  gastric  mucosa,  a  general  lowered  resistance  by  disease  or 
disturbed  nutrition  accompanied  by  a  hypoacidity,  we  have  factors  that 


12 

make  it  possible  for  bacteria  swallowed  or  in  the  blood  stream  to 
become  implanted  in  the  abrasion  and  to  produce  local  inflammation, 
induration,  congestion  and  edema,  and  a  chronic  ulcer.  Further,  it  is 
reasonable  to  believe,  as  observed  and  pointed  out  in  one  animal,  that 
after  the  edges  and  base  of  the  abrasion  have  become  infected,  inflamed 
and  finally  indurated — normal  blood  supply  being  diminished  thereby — 
the  general  condition  of  the  patient  may  improve  or  become  normal, 
and  yet  have  the  ulcer  remain  chronic — because  of  the  local  diminution 
of  blood  supply  and  edema  —  and  even  to  become  more  extensive 
because  of  mechanical  irritation  of  coarse  foods  and  tonic  gastric 
activity  associated  with  the  action  of  acid  pepsin  on  the  devitalized 
tissue  in  the  base  and  about  the  edges  of  the  ulcer ;  or  even  a  reinfection 
may  occur  during  a  period  of  hyposecretion  following  some  digestive 
disturbance. 

It  is  interesting  to  recall  that  acidity  is  generally  considered  the 
all-important  factor  in  the  chronicity  of  the  ulcer,  which  is  hardly 
tenable  in  light  of  my  observations  or  those  of  Rosenow.^®  I  recognize, 
however,  that  the  chronic  ulcer  that  I  report  might  be  considered  by 
some  to  be  different  from  the  ordinary  peptic  ulcer  seen  clinically. 
My  ulcers  may  be  similar  to  those  found  in  some  cases  of  achylia 
gastrica,  which  some  clinicians  believe  to  have  a  different  etiology 
than  peptic  ulcer,  i.  e.,  trophic. 

These  results  explain  the  reports  of  many  investigators  who  have 
ascribed  some  other  cause  to  the  delayed  healing  or  chronicity.  The 
results  of  Durante,^  who  produced  ulcers  chronic  in  character  by  sec- 
tion of  the  splanchnics,  are  in  accord  with  this  conception  when  the 
petechial  hemorrhages,  erosions,  temporary  hypoacidity  and  disturbed 
digestion  and  loss  of  weight,  that  often  results  along  with  the  tem- 
porary lowered  resistance  from  this  operation,  are  taken  into  account. 
Durante  reports  that  his  animals  lived  only  a  short  time,  which  sup- 
ports my  contention.  Our  double  vagotomized  and  splanchnectomized 
dogs  at  this  laboratory  live  indefinitely,  but  their  feeding  has  to  be 
carefully  attended  to  for  the  first  week  or  two — in  a  good  state  of 
health,  which  explains,  I  believe,  why  we  found  no  ulcers  in  our  series. 
Durante's  ulcers  were  infected,  as  was  shown  by  Rosenow.  This  con- 
ception is  also  in  accord  with  the  findings  of  Bolton^^  and  Friedman 
and  Hamburger,^^  who  report  that  partial  pyloric  stenosis  delays  the 
healing  of  ulcer.  The  former  investigator  suggests  that  bacterial  inva- 
sion may  have  been  the  cause.  Both  investigators  report  that  such 
animals  with  partial  pyloric  stenosis  vomit,  lose  weight  and  become 
cachectic.  This  also  occurred  in  some  of  my  dogs.  Bolton  reports  that 
in  some  of  his  animals  the  gastric  contents  were  neutral  or  alkaline, 
but  Friedman  and  Hamburger  state  that  "hyperacidity"  resulted  in 


13 

their  animals.  The  effect  of  pyloric  stenosis  upon  gastric  secretion  has 
not  been  thoroughly  worked  out,  so  this  point  cannot  be  settled. 
Turck's^  results  are  in  agreement  with  this  conception.  Turck  pro- 
duced ulcers  by  feeding  B.  colt  in  large  amounts  over  long  periods  of 
time  to  animals  that  were  confined  and  that  manifested  abnormal 
"systemic  conditions"  with  "modified  conditions  of  the  alimentary 
tract."  I  was  surprised  to  find  that  this  conception  is  not  contrary  to 
Rosenow's  observations.  In  looking  over  his  protocols/®  I  find  that 
the  animals  that  showed  chronic  ulcers  in  his  series  had  distemper  or 
some  general  malaise  as  shown  by  anorexia  and  loss  of  weight.  I  do 
not  accept  the  results  of  Rosenow  as  he  interprets  them  with  respect  to 
chronic  ulcer.  Even  if  his  specificity  idea  is  accepted,  that  does  not 
prove  without  question  of  a  doubt,  that  this  specific  infection  is  the 
cause  of  the  chronicity  of  the  ulcer.  A  mycotic  embolus  is  one  of  the 
factors  causing  acute  gastric  lesions,  or  the  bacteria  may  infect  an 
acute  lesion  otherwise  produced.  But  it  is  agreed  by  most  workers 
that  acute  ulcer  in  healthy  animals  heal  rapidly  no  matter  how  pro- 
duced. So  it  is  very  probable  in  the  light  of  the  results  of  other 
investigators  and  of  the  results  obtained  in  this  study  that  chronic 
gastric  ulcer  has  its  origin  in  an  acute  lesion  of  the  mucous  membrane 
which  is  infected  by  swallowed  bacteria,  or  by  bacteria  from  the  blood 
stream,  during  a  time  at  which  the  mucous  membrane  is  pathologic- 
secreting  none  or  but  little  free  acid — and  the  general  resistance  is 
lowered  by  disease  or  disturbance  of  nutrition. 

3.     METHOD  FOR   MAKING  A  PYLORIC  POUCH   TO  BE  USED   IN   THE   STUDY 

OF   GASTRIC    ULCER 

Although  several  investigators  have  reported  that  they  were  able 
to  produce  ulcers  of  the  chronic  type,  no  one  has  seen  a  chronic  gastric 
ulcer  in  the  process  of  development.  The  method  generally  employed 
has  been  to  produce  an  ulcer  in  the  stomach  by  some  means  and  then 
kill  the  animal  some  time  later  and  ascertain  the  condition  of  the  ulcer. 
Such  a  procedure  is  very  unsatisfactory  experimentally  because  of 
the  presence  of  numerous  uncontrollable  factors.  Hardt^*  and  Drag- 
stedt^^  approached  nearer  to  the  ideal  experimental  procedure  when 
they  studied  ulcer  in  the  Pawlow  pouch.  But  in  the  Pawlow  pouch  one 
is  working  with  a  part  of  the  stomach  that  seldom  has  ulcer,  that 
heals  rapidly,  and  that  produces  an  acid  secretion.  The  mucous  mem- 
brane of  the  pyloric  portion  of  the  stomach,  on  the  other  hand,  is  the 
frequent  site  of  ulcer,  heals  slower  than  the  fundic  mucous  membrane 


24.  Hardt,  L.  L.  J.:    Am.  J.  Physiol.  40:314  (April)  1916. 

25.  Dragstedt,  L.  R. :   J.  A.  M.  A.  68:330  (Feb.  3)  1917. 


14 

and  does  not  produce  an  acid  secretion  but  a  mucous  secretion  slightly- 
alkaline  in  reaction.  So  it  seems  that  the  ideal  experimental  procedure, 
in  which  all  factors  might  be  controlled  and  chronic  ulcer  most  likely 
to  be  produced  under  daily  observation,  would  be  to  study  the  factors 
(acid,  alkalies,  irritation,  motility,  infection,  with  specific  and  non- 
specific bacteria,  emaciation,  etc.)  that  influence  healing,  positively  or 
negatively,  in  a  pouch  of  the  pyloric  portion  of  the  stomach. 

Hence  the  operative  technic  for  making  such  a  pyloric  pouch  has 
been  worked  out. 

METHOD 

Two  methods  are  presented,  one  for  making  a  pouch  with  nerves 
intact,  the  other  for  making  a  pouch  with  extrinsic  nerve  supply 
severed. 

With  Nerve  Supply  of  the  Pouch  Intact. — Approximately  at  a  point 
on  the  anterior  wall  of  the  stomach  where  the  fundic  mucous  mem- 
brane merges  into  the  pyloric  mucous  membrane  an  incision  one  inch 
long  is  made  through  the  wall  into  the  lumen  of  the  stomach  (Fig.  4,  a). 
Through  this  incision  the  mucosa  is  everted  and  the  original  incision 
(a)  is  continued  around  the  stomach  (b),  cutting  only  the  mucosa 
without  cutting  deeper  than  the  submucosa  (as  in  the  Pawlow  opera- 
tion), thus  dividing  the  mucosa  into  fundic  and  pyloric  portions.  Th>; 
anterior  and  posterior  edges  of  the  fundic  mucosa  is  then  sewn  together 
(Fig.  5,  c)  with  a  continuous  Lembert  suture,  as  is  also  the  anterior 
and  posterior  edges  of  the  pyloric  mucosa  (d),  thus  forming  a  wall  of 
the  two  mucous  membranes,  which  divides  the  stomach  into  two  com- 
partments, the  fundic  and  pyloric.  The  incision  in  the  wall  of  the 
stomach  (a)  is  then  closed  by  a  continuous  suture.  Next  a  posterior 
gastro-duodenostomy  (e)  is  done  connecting  the  fundic  compartment 
with  the  duodenum.  Then  a  pylorectomy  (Fig.  6,  f)  is  done  and  the 
pyloric  compartment  is  opened  to  the  outside  by  a  stab  wound  (g), 
the  pyloric  portion  of  the  stomach  being  anchored  to  the  abdominal 
wall  by  a  series  of  interrupted  sutures. 

With  Extrinsic  Nerve  Supply  Severed. — The  pyloric  portion  of  the 
stomach  is  separated  from  the  rest  of  the  stomach  and  from  the  duo- 
denum by  incisions  "A"  and  "B"  (Fig.  7),  care  being  taken  not  to 
interfere  with  the  blood  supply  of  the  pyloric  portion,  which  is  to  be 
the  pouch.  An  end  to  side  anastomosis  (Fig.  8,  a')  of  the  stomach 
to  the  duodenum  is  done  and  the  cut  end  of  the  duodenum  is  closed 
(b').  Then  the  opening  at  the  pyloric  orifice  (b)  is  closed.  Next  a 
large  stab  wound  is  made  in  the  abdominal  wall  and  the  pouch  is 
anchored  in  place.  The  reversal  of  the  pouch  so  that  "a"  is  brought 
to  the  outside  instead  of  "b"  makes  a  larger  rosette  and  the  mucosa 
of  the  pouch  more  accessible. 


15 


Figure  5 


Figure  6 


16 


Figure  7 


Figure 


17 


RESULTS 


Dogs  operated  on  as  described  by  these  methods  Hve  indefinitely 
in  a  good  state  of  health.  Their  feeding  must  be  looked  after  care- 
fully for  the  first  week  or  two.  Bones  should  not  be  fed  until  two  or 
three  months  after  the  operation.  They  cause  obstruction  at  the  point 
of  gastroduodenostomy. 

The  study  of  the  experimental  production  of  chronic  ulcer  and  the 
factors  influencing  the  healing  of  acute  ulcers  is  being  continued  by 
this  method. 

4.     THE    RELATION    OF    THE    LOCATION    OF    THE    ULCER    TO    CHANGES    IN 
MOTILITY   AND    EMPTYING   TIME    OF   THE    STOMACH 

All  clinicians  are  generally  agreed  that  in  duodenal  ulcer  there  is 
a  retention  of  gastric  contents  and  a  hyperperistalsis  of  the  stomach. 
The  literature,  however,  is  somewhat  at  variance  concerning  the 
motility  of  the  stomach  in  ulcers  of  the  pyloric  portion  of  the  stomach, 
unless  a  stenosis  has  been  produced  when  the  effects  upon  motility  are 
practically  identical  with  those  of  a  duodenal  ulcer.  Dundon^^  studied 
the  motility  of  the  empty  stomach  in  the  condition  of  ulcer  of  the 
pyloric  portion  of  the  stomach  and  the  duodenum.  He  concluded 
from  his  work  that  the  motility  of  the  empty  stomach  was  greater  in 
the  condition  of  ulcer  of  the  stomach  and  duodenum. 

Desiring  more  complete  and  definite  data  on  the  relation  of  the 
location  of  the  ulcer  upon  changes  in  motility  and  emptying  time  this 
study  was  undertaken. 

METHODS 

The  motility  of  the  empty  stomach  was  studied  three  to  five  weeks 
previous  to  the  making  of  an  acute  ulcer.  The  criteria  used  were: 
(1)  the  height  of  the  contraction,  (2)  the  frequency,  (3)  the  length 
of  the  hunger  and  rest  periods,  (4)  the  type  of  the  contractions,  and 
(5)  the  postural  and  tonic  activity  of  the  stomach,  the  latter  being 
determined  by  measuring  the  required  amount  of  air  necessary  to  be 
put  into  the  balloon  to  raise  the  manometer  level  one  inch.^^     This 


26.  DundoR,  J.  R.:    Am.  J.  Physiol.  44:234   (Sept.)    1917. 

27.  The  amount  of  air  required  is  practically  constant  from  day  to  day,  never 
varying  more  than  5  c.c.  There  is  quite  a  variation  between  different  dogs, 
varying  from  15  to  40  c.c.  After  section  of  the  vagi  the  amount  required  is 
from  10  to  20  c.c.  more  than  normal.  This  is  only  temporary;  after  from  ten 
to  twelve  days  the  amount  required  becomes  normal  again.  It  is  a  question 
whether  this  is  a  true  measure  of  the  postural  or  tonic  activity  of  the  stomach. 
It  points  in  that  direction,  however.  The  normal  amount  required  is  not 
influenced  by  ulcer  of  the  stomach  or  duodenum.  For  a  day  or  two  after 
making  the  ulcer  the  amount  required  may  be  from  5  to  10  c.c.  below  normal, 
however. 


18 

method  of  putting  a  fixed  amount  of  air  in  the  balloon  gave  a  con- 
stant base  line  from  which  one  could  comparatively  judge  more  accu- 
rately the  character  of  the  motility.  The  size  of  the  balloon,  the  time 
of  starvation,  and  as  far  as  possible,  the  diet  were  controlled.  Bones 
were  not  allowed  to  be  fed  because  they  are  sometimes  found  in  the 
stomach  twenty-four  hours  after  feeding.  The  state  of  nutrition  of 
the  dogs  was  guarded  carefully.  Dogs  with  the  mange,  sniffles,  or 
any  other  disease  were  discarded.  Ulcers  were  made  by  injecting 
1.5  c.c.  of  a  5  per  cent,  silver  nitrate  solution  beneath  the  mucosa. 
Ulcers  were  made  in  the  anterior  wall  of  the  fundus  in  three  dogs,  in 
the  anterior  wall  near  the  lesser  curvature  of  the  pyloric  portion  of 
the  stomach  from  one-half  to  one  inch  proximal  to  the  sphincter  in 
five  dogs  and  in  the  first  inch  of  the  duodenum  in  six  dogs.  Observa- 
tions were  made  on  the  motility  of  the  empty  stomach  for  from  three 
to  seven  weeks  following  the  making  of  the  ulcer. 

Observations  were  also  made  on  the  emptying  time  of  the  stomach 
in  ulcer  of  the  fundic  and  pyloric  portions  of  the  stomach  and  the 
duodenum.  A  meal  of  100  gm.  of  ground  meat  mixed  with  50  c.c.  of 
water  was  fed  and  its  emptying  time  determined  either  by  gastric 
fistula,  emesis  (morphin),  and  in  some  cases  roentgenographically. 


RESULTS 

Ulcer  of  the  fundic  portion  of  the  stomach  had  no  efifect  on  the 
motility  of  the  empty  stomach,  save  a  slight  temporary  inhibition  for 
the  first  two  or  three  days  following  the  making  of  the  ulcer.  The 
same  held  true  for  the  emptying  time,  no  delay  occurring.  Healed 
ulcers  were  found  at  necropsy. 

TABLE  3. — Motility  of  the  Stomach  Before  and  After  Ulcer  of  the  Duo- 
denum ;   Twenty-Four  Hours'"  Starvation 


Dog 

Average 
Height  of 
Contraction 

Type 

Average 

Length  of 

Hunger  Period 

Average 
Length  of 
Rest  Period 

IX 

Before 
1         After 

5  cm. 
7  cm. 

I 
I,  II,  III 

40  min. 
2  hrs. 

11/2  hrs. 
Ihr. 

XII* 

Before 
After 

J    Had  to  starve 
1    80  hrs.  hefore 
contractions 
S         occurred 
5.5  cm. 

I,  II 

30  min. 

Ihr. 

XVI 

Before 

After 

7  cm. 
9  cm. 

I,  II 
I,  II,  III 

1V4  hrs. 
3  hrs. 

IVi  hrs. 
30  min. 

XXI 

Before 
After 

4.5  cm. 
9.5  em. 

I 
I,  II,  III 

114  hrs. 
2%  hrs. 

2  hrs. 
1%  hrs. 

XXXTI 

Before 
After 

5  cm. 
5  cm. 

I 

I,  II,  in 

50  min. 
3  hrs. 

214  hrs. 
1V&  hrs. 

XXXIII 

Before 

After 

5  cm. 
7  cm. 

I 
I,  II,  III 

Ihr. 
3  hrs. 

3  hrs. 
Ihr. 

An   old   animal. 


19 

Ulcer  of  the  pyloric  portion  of  the  stomach  caused  in  three  out  .of 
five  dogs  an  increase  in  the  motility  of  the  empty  stomach.  Here,  too, 
a  temporary  inhibition  of  the  motility  for  two  or  three  days  following 
the  making  of  the  ulcer  occurred.  The  emptying  time  of  the  stomach 
was  only  interfered  with  in  one  of  the  dogs,  in  which  there  was  a 
delay  of  two  hours.  In  this  dog  at  necropsy  an  extensive  scar  was 
found  extending  to  the  pyloric  sphincter,  but  not  involving  it. 

TABLE   4. — Showing   Emptying   Time  of  the   Stomach   Before   and   After 
Ulcer  of  the  Duodenum 


Normal 

Emptying 

Time 

Dog 

Time  of 
Emptying 

Time  after 
Ulcer,  Duo. 

Delayed 

Remarks 

IX 

3  hrs. 

51/2  hrs. 

21/2  hrs. 

XII 

SVz  hrs. 

5  hrs. 

11/2  hrs. 

XVI 

3  hrs. 

514  hrs. 

2%  hrs. 

XXI 

2%  hrs. 

51/2  hrs. 

2%  hrs. 

XXXII 

4  hrs. 

9  hrs. 

5  hrs. 

On  a  full  meal  this  dog  often  had 
food  in  the  stomach  24  hours  after 
feeding 

XXXIII 

3%  hrs. 

5  hrs. 

1%  hrs. 

Ulcer  located  in  the  first  inch  of  the  duodenum  caused  an  increase 
in  the  motility  of  the  empty  stomach  in  all  of  the  six  dogs  (Table  3, 
Figs.  9,  10,  11  and  12).  This  increase  was  very  marked  in  three  of 
them.  A  delayed  emptying  time  was  observed  (Table  4)  in  every 
animal.  One  animal  showed  a  high  grade  retention  to  the  degree  that 
frequently  food,  that  is  on  a  full  meal,  was  present  in  the  stomach 
twenty-four  hours  after  feeding.  The  hypermotility  and  retention 
only  lasted  from  two  to  four  weeks.  On  all  these  animals  a  necropsy 
was  done  and  scars  were  found. 

DISCUSSION 

These  results  show  that  the  clinical  symptoms  of  chronic  ulcer 
with  respect  to  disturbed  motility  and  emptying  time  of  the  stomach 
can  practically  be  duplicated  experimentally  by  an  acute  ulcer.  The 
inhibition  occurring  for  two  or  three  days  after  making  the  ulcer  is 
explained  by  the  observations  of  Luckhardt^^  to  the  effect  that  gastritis 
inhibits  motility,  for  a  temporary  gastritis  is  produced  about  the  area 
of  the  injection  of  the  silver  nitrate.  Why  ulcer  of  the  pyloric  portion 
of  the  stomach  and  duodenum  should  disturb  motility  and  ulcer  of  the 
fundic  portion  of  the  stomach  is  a  question  yet  to  be  answered. 


28.  Luckhardt:    loc.  cit.  Carlson,  The  Control  of  Hunger  in  Health  and  Dis- 
ease, Chicago,  1916. 


O 


o    " 
O    O 


o 
•a 


bo 


o 

p 


c 
o 

u 


bo 


22 

5.     IS    HYPERMOTILITY    AND    DELAYED    EMPTYING    OF    THE    STOMACH    IN 

DUODENAL    ULCER    DUE    TO    AN    INTRINSIC    OR 

EXTRINSIC    MECHANISM? 

Hypermotility  and  delayed  emptying  of  the  stomach  as  a  result 
of  duodenal  ulcer  may  be  caused  by  either  one  or  a  combination  of 
four  mechanisms :  (1)  to  a  long  reflex  to  the  cord  and  medulla,  (2)  to 
a  short  reflex  to  the  celiac  ganglion,  (3)  to  a  local  intrinsic  reflex, 
(4)  or  to  an  altered  metabolic  rate.  Carlson^®  and  Cannon^"-  have 
shown  that  the  isolated  empty  or  full  stomach,  that  is,  with  the 
extrinsic  nerves  sectioned,  manifests  normal  movements.  The  move- 
ments of  the  isolated  empty  stomach  are  chiefly  Type  I,  Types  II  and 
III,  contractions  seldom  appearing.  Brunemeier  and  Carlson^^  found 
that  inhibition  of  contractions  by  acids,  alkalies,  water,  milk,  etc.,  occur 
in  the  isolated  stomach,  showing  that  it  was  possible  to  inhibit  move- 
ments of  the  stomach  via  local  or  short  nerve  paths.  Hicks  and 
Vischer^^  showed  that  duodenal  regurgitation  when  acid  was  in  the 
stomach  and  that  the  characteristic  movements  by  which  this  was 
accomplished  occurred  in  the  isolated  stomach  and  duodenum.  But 
the  literature  presents  no  evidence  as  to  whether  augmentation,  or 
increased  motility,  can  be  brought  about  by  local  reflexes.  On  the 
other  hand,  the  literature  draws  our  attention  to  the  importance  of 
the  extrinsic  mechanism  and  uses  the  vagus  nerve  to  explain  all  con- 
ditions of  hypermotility,  retention,  pylorospasms,  etc.,  without  con- 
sidering the  possible  importance  of  an  intrinsic  mechanism. 

METHODS 

Both  vagi  and  splanchnics  were  sectioned  and  the  celiac  plexus  was 
extirpated.  Records  were  made  of  the  motility  of  the  empty  stomach, 
using  the  criteria  mentioned  in  Study  3.  An  acute  ulcer  was  made  in 
the  first  inch  of  the  duodenum  and  changes  in  motility  were  observed. 

Observations  were  made  on  the  emptying  time  of  the  stomach 
before  and  after  the  ulcer.  A  meal  of  100  gm.  of  ground  meat  mixed 
with  50  c.c.  of  water  was  fed. 

RESULTS 

An  increase  in  the  motility  of  the  isolated  empty  stomach  occurred 
(Table  5)  following  the  making  of  the  acute  ulcer  in  the  duodenum 
(Figs.  13,  14,  15  and  16).  The  degree  of  increase  was  not  as  great 
as  that  noticed  when  the  extrinsic  nerves  were  intact  (Table  3).     All 


29.  Carlson,  A.  J.:    Am.  J.  Physiol.  32:369,  1913. 

30.  Cannon,  W.  B.:    Am.  J.  Physiol.  36:191,  1915. 

31.  Brunemeier  and  Carlson:    Am.  J.  Physiol.  36:191,  1915. 

32.  Hicks  and  Vischer :    Am.  J.  Physiol.  39:1,  1915. 


23 

TABLE  5. — Motility  OF  the  Stomach  Before  and  After  Ulcer  of  the  Duo- 
denum IN  Dogs  with   Both  Vagi  and  Splanchnics  Sectioned 
AND    Celiac    Plexus    Extirpated,    Twenty-Four 
Hours'  Starvation 


Dog 

Average 

Height  of 

Contraction 

Type 

Average 

Length  of 

Hunger  Period 

Average 
Length  of 
Rest  Period 

I 

Before 
After 

6  cm. 
9  em. 

I 
I 

1  hr.  40  min. 
3  hrs.  20  min. 

2  hrs. 
2  hrs. 

I-A 

Before 
After 

4  cm. 
8  cm. 

I 
I 

Ihr. 
2  hrs. 

Ihr. 

45  min. 

XXXIII 

Before 
After 

Contraction 
negligible 
on  24  hrs. 

starvation 
8  cm. 

I 

3  hrs. 

30  min. 

XXI 

Before 
After 

5  cm. 

7  cm. 

I 
I 

30  min. 
aV^  hrs. 

ly,  hrs. 
20  min. 

Fig.  13.^Contractions  from  Dog  33  (Tables  5  and  6)  with  both  vagi  and 
splanchnic  sectioned  and  celiac  plexus  extirpated  and  starved  twenty-four  hours. 
Note  type  of  contractions  in  the  isolated  stomach. 


TABLE  6. — Showing   Emptying   Time  of   the   Stomach   Before  and   After 
Ulcer  of  the  Duodenum  in  Dogs  with  Both  Vagi  and  Splanch- 
nics Sectioned  and  Celiac  Plexus  Extirpated 


Dog 

Normal  Time  of 

Emptying  of  Isolated 

Stomach 

Emptying  Time 
after  Ulcer  of                    Time  Delayed 
Duodenum 

I-A 

XXXIII 

XXI 

314  hrs. 
3%  hrs. 
3  hrs. 

4%  hrs.                               1%  hrs. 
5  hrs.                                2%  hrs. 
5  hrs.                                    2  hrs. 

be 

E 


> 
6 


Q 


u 


bo 


26 

contractions  were  Type  I,  showing  that  the  prevalence  of  Types  II 
and  III  in  normal  animals  (Table  3)  with  duodenal  ulcer  was  due  to 
an  extrinsic  mechanism. 

The  emptying  of  the  stomach  was  delayed  (Table  6),  not  so  much 
as  when  the  extrinsic  nerves  were  intact  (Table  4). 

During  the  course  of  this  study  Brunemeier  and  Carlson's^^  obser- 
vations on  the  inhibitory  effect  of  alkalies  and  acids  on  the  motility 
of  the  isolated  stomach  was  repeated  and  confirmed. 

DISCUSSION 

These  results  show  that  the  fundamental  cause  of  the  gastric  hyper- 
motility  and  delayed  emptying  of  the  stomach  in  duodenal  ulcer  is 
intrinsic,  and  that  it  is  enhanced  by  the  presence  of  the  extrinsic  ner- 
vous mechanism,  the  role  of  the  latter  being  to  increase  the  frequency 
of  the  contractions  occuring  on  gastric  tone,  or  Types  II  and  III. 

Although  these  results  show  that  hypermotility  and  delayed  empty- 
ing of  the  stomach  in  duodenal  ulcer  are  due  to  intrinsic  mechanism, 
they  do  not  teach  us  the  nature  of  the  mechanism.  There  are  two 
possibilities :  ( 1 )  an  increased  irritability  of  the  intrinsic  nervous 
reflex,  and  (2)  an  altered  metabolic  rate. 

ADDENDUM 

Since  writing  this  article  my  attention  has  been  called  to  an  article 
by  Carman^^  in  which  he  differentiates  between  extrinsic  and  intrinsic 
spasm  by  the  use  of  atropin.  He  states  that  "intrinsic  spasm  plays  an 
important  part  in  the  roentgenologic  evidence  of  duodenal  ulcers,  and 
that  in  the  absence  of  spasm  no  deformity  of  the  bulb  would  be  seen 
in  many  instances,  and  the  case  passed  as  negative."  It  is  very  inter- 
esting and  important  to  note  that  my  experimental  results  corroborate 
this  clinical  finding. 


33.  Carman,  R.  D. :    J.  A.  M.  A.  66:1283  (April  22)   1916. 


r  X     -■  _      ^         .  1   '1 


-\^ 


